[ CAS No. 1224844-66-9 ] {[proInfo.proName]}

Name: 1224844-66-9|5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine|97+%
Brand: Ambeed
SKU: A125736
Price: 75.0 USD
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Quality Control of [ 1224844-66-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1224844-66-9 ]

SDS Specification

Alternatived Products of [ 1224844-66-9 ]

Product Details of [ 1224844-66-9 ]

CAS No. :	1224844-66-9	MDL No. :	MFCD13182075
Formula :	C₁₃H₁₇BN₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QAFVXRPBLZCHKP-UHFFFAOYSA-N
M.W :	260.10	Pubchem ID :	46199575
Synonyms :

Calculated chemistry of [ 1224844-66-9 ]

Physicochemical Properties

Num. heavy atoms :	19
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.46
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	74.89
TPSA :	70.51 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.18 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.4
Log Po/w (WLOGP) :	1.72
Log Po/w (MLOGP) :	0.9
Log Po/w (SILICOS-IT) :	1.02
Consensus Log Po/w :	1.21

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.25
Solubility :	0.147 mg/ml ; 0.000563 mol/l
Class :	Soluble
Log S (Ali) :	-3.52
Solubility :	0.0781 mg/ml ; 0.0003 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.16
Solubility :	0.0181 mg/ml ; 0.0000695 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.24

Safety of [ 1224844-66-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302+H312+H332-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1224844-66-9 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 1224844-66-9 ]
Downstream synthetic route of [ 1224844-66-9 ]

[ 1224844-66-9 ] Synthesis Path-Upstream 1~7

1
[ 73183-34-3 ]
[ 64037-07-6 ]
[ 1224844-66-9 ]

Yield	Reaction Conditions	Operation in experiment
89.5%	With dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium cesium chloride; potassium acetate In 1,4-dioxane for 3 h; Inert atmosphere; Reflux	Specific operation: Put 127g of compound 4, 182g of bis-boronate,45 g of 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (dppf cesium chloride) and 180 gPotassium acetate was added to 2L of 1,4-dioxane and the mixture was refluxed under nitrogen for 3 hours, cooled to room temperature, filtered and concentrated to give crude compound 5. The crude compound 5 was dissolved in 500 ml of petroleum ether and stirred for 1 hour. , filtration, vacuum drying at 50° C. to obtain 110 g of compound 6, with a yield of 89.5percent.
85.3%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 20 - 110℃; for 2 h; Inert atmosphere	5-Bromobenzo[d]oxazol-2-amine (4) (15.0 g, 70.4 mmol) and bis(pinacolato)diboron (21.5 g, 84.5mmol,l.2 eq) were dissolved in 1,4-dioxane (150 mL). To this mixture, PdCh(dppf) (5.17 g, 6.3 mmol, 0.09 eq)and potassium acetate (20.71 g, 211 mmol, 3 eq) were added sequentially. The resulting mixture was degassedand back-filled with argon three times and then refluxed at ll ooc for 2 h with stirring. The mixture was allowedto cool to room temperature, filtered, and the cake was rinsed with ethyl acetate (30 mL x 2). The filtrate was20 mixed with silica gel (50 g) and then concentrated in vacuo. The residue was loaded onto a plug of silica gel (60g), eluted with ethyl acetate/heptane (l: l, 1000 mL ). The filtrate was concentrated in vacuo, the residue wassuspended in heptane (50 mL) and refluxed for 30 min with stirring. The suspension was cooled to roomtemperature, and then the solid was collected by filtration and rinsed with small amount of heptane to afford thedesired product 5 (15.66 g, 85.3percent yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): i5 7.47 (s, lH), 7.4325 (s, 2H), 7.34 (s, 2H), 1.30 (s, 12H).
43%	With potassium acetate In Petroleum ether	Step 7: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine A mixture of 5-bromobenzo[d]oxazol-2-amine (20.0 g, 93.9 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (28.6 g, 113 mmol), 1,1'-bis(diphenylphosphino)ferrocenyl palladium (II) dichloride (6.87 g, 9.39 mmol) and potassium acetate (27.6 g, 282 mmol) in DMF (200 mL) was stirred at 80° C. for 6 h under nitrogen. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 0-50percent ethyl acetate in petroleum ether) to yield 10.5 g (43percent) of the title compound as a brown solid. LCMS (ESI): [M+H]⁺=261.

Reference： [1] Patent: CN105130973, 2018, B, . Location in patent: Paragraph 0053; 0069-0071
[2] Patent: WO2013/23184, 2013, A1, . Location in patent: Paragraph 00233; 00234
[3] Patent: US2018/65983, 2018, A1,
[4] Patent: WO2010/51042, 2010, A1, . Location in patent: Page/Page column 27; 133; 219
[5] Patent: WO2013/71272, 2013, A1, . Location in patent: Paragraph 00256-00275
[6] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00502
[7] Patent: US2014/357651, 2014, A1, . Location in patent: Paragraph 0485
[8] Patent: US9174994, 2015, B2, . Location in patent: Page/Page column 116
[9] Patent: US9174994, 2015, B2, . Location in patent: Page/Page column 120
[10] Patent: WO2016/206101, 2016, A1, . Location in patent: Page/Page column 76; 77

2
[ 40925-68-6 ]
[ 1224844-66-9 ]

Reference： [1] Patent: WO2013/71272, 2013, A1,
[2] Patent: WO2013/23184, 2013, A1,
[3] Patent: WO2014/151147, 2014, A1,
[4] Patent: WO2014/151147, 2014, A1,
[5] Patent: US2014/357651, 2014, A1,
[6] Patent: US2014/357651, 2014, A1,
[7] Patent: US9174994, 2015, B2,
[8] Patent: US9174994, 2015, B2,
[9] Patent: CN105130973, 2018, B,

3
[ 106-41-2 ]
[ 1224844-66-9 ]

Reference： [1] Patent: WO2014/151147, 2014, A1,
[2] Patent: WO2014/151147, 2014, A1,
[3] Patent: US2014/357651, 2014, A1,
[4] Patent: US2014/357651, 2014, A1,
[5] Patent: US9174994, 2015, B2,
[6] Patent: US9174994, 2015, B2,
[7] Patent: CN105130973, 2018, B,

4
[ 7693-52-9 ]
[ 1224844-66-9 ]

5
[ 1404480-03-0 ]
[ 1224844-66-9 ]

Reference： [1] Patent: WO2014/151147, 2014, A1,
[2] Patent: US2014/357651, 2014, A1,
[3] Patent: US9174994, 2015, B2,

6
[ 1224844-66-9 ]
[ 1224844-38-5 ]

Yield	Reaction Conditions	Operation in experiment
67.3%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In 1,4-dioxane; water at 20 - 110℃; for 3 h; Inert atmosphere	3-Bromo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2) (20 g, 78.1 mmol) and 5-( 4,4,5,5-15 tetramethyl-1,3,2-dioxaborolan-2-yl)benzo [d]oxazol-2-amine (5) (26.4 g, 102 mmol,l.3 eq) were dissolved in amixture of 1,4-dioxane and water (300 mL/100 mL). To this mixture Pd(PPh3) 4 (7.21 g, 6.25 mmol, 0.08 eq) andsodium carbonate (41.4 g, 391 mmol, 5 eq) were added sequentially. The resulting mixture was degassed andback-filled with argon three times and then refluxed at 110°C for 3 h with stirring. The mixture was allowed tocool to room temperature, filtered and the cake was washed with ethyl acetate (50 mL x 2). The combined20 filtrate was concentrated in vacuo. The residue was suspended in a mixture of water and ethyl acetate (500mL/100 mL) and stirred for 30 min. The solid was collected by filtration, rinsed with water (50 mL) and ethylacetate (100 mL). The crude product thus obtained was suspended in ethyl acetate (100 mL) and stirred for 30min. The solid was collected by filtration, rinsed with ethyl acetate (50 mL), and dried in vacuo to afford thecrude product of Formula I(20 g, 83percent yield). The above obtained product (20 g) was dissolved in refluxing25 methanol (1600 mL), and activated charcoal (6 g, 30percent W/W) was added. The mixture was refluxed for 30 min,and then the hot mixture was filtered through a Buchner funnel. The cake was washed with hot methanol (1 00mL x 3). The combined filtrates were concentrated. The solid was slurried in ethyl acetate (300 mL), and thesuspension was stirred at room temperature for 30 min. The solid was collected by filtration, washed with ethylacetate (50 mL x 2), and dried in vacuo to afford the desired product of Formula I as polymorph Form A30 (16.27g, 67.3percent yield). m.p.: 273.67 oc (Onset Temperature); 1H NMR (400 MHz, DMSO-d6): i5 8.26 (s, 1H,pyrimidine), 7.56 (s, 2H, oxazol-2-amine), 7.48 (d, J = 8.1 Hz, 1H, Ph), 7.45 (d, J = 1.4 Hz, 1H, Ph), 7.27 (del, J= 8.1, 1.6 Hz, 1H, Ph), 5.08 (m, 1H, iPr) and 1.52 (d, J = 6.7 Hz, 6H, iPr); 13C NMR (100 MHz, DMSO-d6): i5163.4, 158.1, 155.4, 153.2, 148.3, 144.4, 143.7, 128.8, 120.5, 115.0, 108.8, 97.5, 48.0 and 21.8; analysis(percentcalcd, percent found for C15H15N70): C (58.24, 58.04), H (4.87, 4.83), N (31.70, 31.49); greater than 99percent purity35 based on LC-MS analysis.

Reference： [1] Patent: WO2013/23184, 2013, A1, . Location in patent: Paragraph 00237; 00238

7
[ 1224844-66-9 ]
[ 1268454-23-4 ]

Reference： [1] Patent: WO2013/71272, 2013, A1,

[ 1224844-66-9 ] Synthesis Path-Downstream 1~88

1
[ 73183-34-3 ]
[ 64037-07-6 ]
[ 1224844-66-9 ]

Yield	Reaction Conditions	Operation in experiment
89.5%	With dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium cesium chloride; potassium acetate; In 1,4-dioxane; for 3h;Inert atmosphere; Reflux;	Specific operation: Put 127g of compound 4, 182g of bis-boronate,45 g of 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (dppf cesium chloride) and 180 gPotassium acetate was added to 2L of 1,4-dioxane and the mixture was refluxed under nitrogen for 3 hours, cooled to room temperature, filtered and concentrated to give crude compound 5. The crude compound 5 was dissolved in 500 ml of petroleum ether and stirred for 1 hour. , filtration, vacuum drying at 50 C. to obtain 110 g of compound 6, with a yield of 89.5%.
85.3%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 20 - 110℃; for 2h;Inert atmosphere;	5-Bromobenzo[d]oxazol-2-amine (4) (15.0 g, 70.4 mmol) and bis(pinacolato)diboron (21.5 g, 84.5mmol,l.2 eq) were dissolved in 1,4-dioxane (150 mL). To this mixture, PdCh(dppf) (5.17 g, 6.3 mmol, 0.09 eq)and potassium acetate (20.71 g, 211 mmol, 3 eq) were added sequentially. The resulting mixture was degassedand back-filled with argon three times and then refluxed at ll ooc for 2 h with stirring. The mixture was allowedto cool to room temperature, filtered, and the cake was rinsed with ethyl acetate (30 mL x 2). The filtrate was20 mixed with silica gel (50 g) and then concentrated in vacuo. The residue was loaded onto a plug of silica gel (60g), eluted with ethyl acetate/heptane (l: l, 1000 mL ). The filtrate was concentrated in vacuo, the residue wassuspended in heptane (50 mL) and refluxed for 30 min with stirring. The suspension was cooled to roomtemperature, and then the solid was collected by filtration and rinsed with small amount of heptane to afford thedesired product 5 (15.66 g, 85.3% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): i5 7.47 (s, lH), 7.4325 (s, 2H), 7.34 (s, 2H), 1.30 (s, 12H).
43%	With potassium acetate; In Petroleum ether;	Step 7: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine A mixture of 5-bromobenzo[d]oxazol-2-amine (20.0 g, 93.9 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (28.6 g, 113 mmol), 1,1'-bis(diphenylphosphino)ferrocenyl palladium (II) dichloride (6.87 g, 9.39 mmol) and potassium acetate (27.6 g, 282 mmol) in DMF (200 mL) was stirred at 80 C. for 6 h under nitrogen. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate in petroleum ether) to yield 10.5 g (43%) of the title compound as a brown solid. LCMS (ESI): [M+H]+=261.

	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 18 - 103℃;Inert atmosphere; Reflux; Large scale;	[00258] 1. 5-Bromobenzo[b]oxazol-2-amine (Compound 2, 13400 g), bis-(pinacolato)diboron (19168 g), and 1,4-Dioxane (134 L) were added to an appropriately sized reactor and stirred at room temperature (-18 to 20 C).[00259] 2. With stirring, the reaction mixture was sparged with nitrogen for -10 minutes at [00260] 3. l,l'-Bis[(Diphenylphosphino) ferrocene dichloropalladium (II) complexed with dichloromethane ((PdC^dppf ), 2569 g)) and potassium acetate (KOAc, 18520 g) were added to the reactor.[00261] 4. With stirring, the sparging with nitrogen was continued for -10 minutes at [00262] 5. The reaction mixture was heated to reflux (100 to 103 C) under slight nitrogen blanket and stirred for 3 to 5 hours.[00263] 6. The reaction was monitored by HPLC.[00264] 7. Upon completion, the reaction mixture was cooled to 18-20 C, filteredthrough a plug of silica gel (40.5 Kg; -30 wt%).[00265] 8. The product was further eluted with Ethyl acetate (37 mL / g) under slight vacuum.[00266] 9. The last eluting fraction of the sample was submittedfor TLC analysis.[00267] 10. The combined filtrates were concentrated under vacuum at 30-40 C to a minimum stirrable volume[00268] (total -1.5 to 2 volumes).[00269] 11. 50% Aq. hydrochloric acid (1 : 1, Cone HCl: H20, 10 mL / g, 67 L of Cone. HClwith 67 L of Water) was charged to the thick slur in the reactor and the reaction mixture was heated to 80 to 84C followed by stirring for 2- 4 hours at 80 to 84 C.[00270] 12. The reaction was monitored by HPLC.[00271] 13. Upon completion, the reaction mixture was cooled to 18-20 C.[00272] 14. A solid was collected via vacuum filtration and washed with 10% aqueous hydrochloric acid (1 :9, ConeHCl: H20) (13 L of Cone. HCl with 67 L of Water).[00273] 15. The light brown to brown solids (wet) was suspended in ethyl acetate (134 L) and stirredfor -30 minutes at 18-20 C.[00274] 16. The solids was collected via vacuum filtration and washed with ethyl acetate (67 L).[00275] 17. The solids was dried for -1 hour under nitrogen blanket and then dried in a vacuum oven at-50 C to constant weight (-72 to 90 hours) with a slight nitrogen bleed to give compound 3 as a brown to light brown color solid (9479 g, 70% yield; HPLC purity 94.2%; 'HNMR (DMSO-d6, 300 MHz) ? 10.2- 9.5 (1H), 7.85-7.71 (1H), 7.62-7.50 (1H)).
	With chloro[(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) second generation; potassium acetate; In 1,4-dioxane; at 80℃; for 16h;	In the reaction vessel 5-bromobenzo[d]oxazol-2-amine (lg, 4.69 mmol) and 4,4,4?,4?,5 ,5 ,5?,S ?-octamethyl-2,2?-bi( 1,3 ,2-dioxaborolane) (1.788 g, 7.04 mmol) were combined, followed by 2nd Generation PCy3 precatalyst (551 mg, 0.93 9 mmol) and potassium acetate (1.382 g, 14.08 mmol). Then dry 1,4-Dioxane (25 mL) was added to this flask. This mixture was degassed and then heated at 80C for 16 hr (monitored by LCMS until all SM was consumed). LC-MS showed the desired mass. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 20 ml ethyl acetate, and extracted with 2N HC1 (2x150 ml). The aqueous was concentrated under reduced pressure. The crude material was applied onto silica gel column with ethyl acetatepetroleum ether (1:1) to affordthe title compound: LCMS (ESI) calc?d for C,3H,7BN203 [M + H]:261,found 261; ?H NMR (400 MHz,CDC13):oe7.78 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.28-7.26 (m,1H), 5.98 (bs, 2H), 1.35-1.37 (m, 12H).

Reference： [1]Patent: CN105130973,2018,B .Location in patent: Paragraph 0053; 0069-0071
[2]Patent: WO2013/23184,2013,A1 .Location in patent: Paragraph 00233; 00234
[3]Patent: US2018/65983,2018,A1
[4]Patent: WO2010/51042,2010,A1 .Location in patent: Page/Page column 27; 133; 219
[5]Patent: WO2013/71272,2013,A1 .Location in patent: Paragraph 00256-00275
[6]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00502
[7]Patent: US2014/357651,2014,A1 .Location in patent: Paragraph 0485
[8]Patent: US9174994,2015,B2 .Location in patent: Page/Page column 116
[9]Patent: US9174994,2015,B2 .Location in patent: Page/Page column 120
[10]Patent: WO2016/206101,2016,A1 .Location in patent: Page/Page column 76; 77

2
[ 1224844-66-9 ]
[ 1404480-15-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In water; at 80 - 84℃;Large scale;	[00258] 1. 5-Bromobenzo[b]oxazol-2-amine (Compound 2, 13400 g), bis-(pinacolato)diboron (19168 g), and 1,4-Dioxane (134 L) were added to an appropriately sized reactor and stirred at room temperature (-18 to 20 C).[00259] 2. With stirring, the reaction mixture was sparged with nitrogen for -10 minutes at [00260] 3. l,l'-Bis[(Diphenylphosphino) ferrocene dichloropalladium (II) complexed with dichloromethane ((PdC^dppf ), 2569 g)) and potassium acetate (KOAc, 18520 g) were added to the reactor.[00261] 4. With stirring, the sparging with nitrogen was continued for -10 minutes at [00262] 5. The reaction mixture was heated to reflux (100 to 103 C) under slight nitrogen blanket and stirred for 3 to 5 hours.[00263] 6. The reaction was monitored by HPLC.[00264] 7. Upon completion, the reaction mixture was cooled to 18-20 C, filteredthrough a plug of silica gel (40.5 Kg; -30 wt%).[00265] 8. The product was further eluted with Ethyl acetate (37 mL / g) under slight vacuum.[00266] 9. The last eluting fraction of the sample was submittedfor TLC analysis.[00267] 10. The combined filtrates were concentrated under vacuum at 30-40 C to a minimum stirrable volume[00268] (total -1.5 to 2 volumes).[00269] 11. 50% Aq. hydrochloric acid (1 : 1, Cone HCl: H20, 10 mL / g, 67 L of Cone. HClwith 67 L of Water) was charged to the thick slur in the reactor and the reaction mixture was heated to 80 to 84C followed by stirring for 2- 4 hours at 80 to 84 C.[00270] 12. The reaction was monitored by HPLC.[00271] 13. Upon completion, the reaction mixture was cooled to 18-20 C.[00272] 14. A solid was collected via vacuum filtration and washed with 10% aqueous hydrochloric acid (1 :9, ConeHCl: H20) (13 L of Cone. HCl with 67 L of Water).[00273] 15. The light brown to brown solids (wet) was suspended in ethyl acetate (134 L) and stirredfor -30 minutes at 18-20 C.[00274] 16. The solids was collected via vacuum filtration and washed with ethyl acetate (67 L).[00275] 17. The solids was dried for -1 hour under nitrogen blanket and then dried in a vacuum oven at-50 C to constant weight (-72 to 90 hours) with a slight nitrogen bleed to give compound 3 as a brown to light brown color solid (9479 g, 70% yield; HPLC purity 94.2%; 'HNMR (DMSO-d6, 300 MHz) ? 10.2- 9.5 (1H), 7.85-7.71 (1H), 7.62-7.50 (1H)).

Reference： [1]Patent: WO2010/51042,2010,A1 .Location in patent: Page/Page column 136
[2]Patent: WO2013/71272,2013,A1 .Location in patent: Paragraph 00256-00275

3
[ 1224844-66-9 ]
[ 1260090-51-4 ]
[ 1260090-97-8 ]
[ 1260090-98-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate; sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 90℃; for 2h;Inert atmosphere;	Example 110Preparation of 5-((S)-7-(2-methoxyethyl)-7-methyl-4-((S)-3-methylmorpholino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)benzo[d]oxazol-2-amine (he1) and 5-((R)-7-(2-methoxyethyl)-7-methyl-4-((S)-3-methylmorpholino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)benzo[d]oxazol-2-amine (he2) A mixture of tetrakis(triphenylphosphine)pallaium(0) (0.0453 g, 0.0000392 mol), sodium carbonate (0.0781 g, 0.000737 mol), and potassium acetate (0.0947 g, 0.000965 mol) were combined and purged with nitrogen. To the mixture was added 2-chloro-7-(2-methoxyethyl)-7-methyl-4-((S)-3-methylmorpholino)-5,7-dihydrofuro[3,4-d]pyrimidine (gn) (0.152 g, 0.000464 mol;) and <strong>[1224844-66-9]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine</strong> (0.150 g, 0.000577 mol) in dry acetonitrile (3.40 mL, 0.0651 mol;) and deoxygenated water (2.00 mL, 0.111 mol). The mixture was heated at 90 C. and stirred for 2 days. The mixture was partitioned between water (50 mL) and 10% methanol in dichloromethane (50 mL). The phases were separated and the aq. extracted with 10% methanol in dichloromethane (2×50 mL). The combined organic phases were dried (MgSO4), filtered, and chromatographed ISCO (12 g, 10-50% ethyl acetate in heptane followed by 5% methanol in dichloromethane) to give 5-(7-(2-methoxyethyl)-7-methyl-4-((S)-3-methylmorpholino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)benzo[d]oxazol-2-amine as a mixture of two diastereomers. The diastereomers were separated by super critical fluid chromatograph to give 18.3 mg and 19.2 mg of each diastereomer (he1) and (he2). Diastereomer 1 LC-MS: m/z=426 (M+H). 1H NMR (400 MHz, DMSO) delta 8.14 (d, J=1.5, 1H), 8.06 (dd, J=8.4, 1.6, 1H), 7.45 (s, 2H), 7.38 (d, J=8.4, 1H), 5.19 (d, J=11.8, 1H), 5.09 (d, J=11.8, 1H), 4.26 (s, 1H), 4.07-3.90 (m, 2H), 3.77-3.63 (m, 2H), 3.56-3.47 (m, 1H), 3.47-3.39 (m, 1H), 3.39-3.20 (m, 2H), 3.14 (s, 3H), 2.14-1.95 (m, 2H), 1.39 (s, 3H), 1.26 (d, J=6.8, 3H). Diastereomer 2 LC-MS: m/z=426 (M+H). 1H NMR (400 MHz, DMSO) delta 8.14 (d, J=1.4, 1H), 8.06 (dd, J=8.3, 1.6, 1H), 7.45 (s, 2H), 7.38 (d, J=8.4, 1H), 5.20-5.07 (m, 2H), 4.26 (s, 1H), 4.09-3.90 (m, 2H), 3.77-3.63 (m, 2H), 3.57-3.48 (m, 1H), 3.47-3.40 (m, 1H), 3.39-3.20 (m, 2H), 3.14 (s, 3H), 2.11-1.95 (m, 2H), 1.40 (s, 3H), 1.27 (d, J=6.7, 3H).

Reference： [1]Patent: US2010/331305,2010,A1 .Location in patent: Page/Page column 88

4
[ 1224844-66-9 ]
[ 6188-23-4 ]
[ 1268453-96-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; for 2h;Reflux;	Compound 1-2 is coupled to a <strong>[1224844-66-9]benzoxazolyl boronic acid ester</strong> in Suzuki conditions to produce compound 1-4.
73%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; for 2h;Reflux;	j0554] The scheme above describes the synthesis of a compound of the invention. A substituted pyridine such as compound 1-1 is reacted with 2-chloroacetaldehyde, resulting in the halogenated imidazopyridine compound 1-2. Compound 1-2 is coupled to a <strong>[1224844-66-9]benzoxazolyl boronic acid ester</strong> in Suzuki conditions to produce compound 1-4. Further derivatization of compound 1-4 using, for example, NBS, DMF results in halogenation of the imidazopyridine moiety, which is then further reacted in an additional Suzuki coupling using pyridine boronic acid to result in compound 1-6.

Reference： [1]Patent: WO2012/116237,2012,A2 .Location in patent: Page/Page column 118
[2]Patent: US2015/320727,2015,A1 .Location in patent: Paragraph 0553; 0554
[3]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[4]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 66
[5]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 343

5
2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile [ No CAS ]
[ 1224844-66-9 ]
[ 1395145-15-9 ]

Yield	Reaction Conditions	Operation in experiment
58%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; N,N-dimethyl-formamide; for 2h;Reflux;	The desired compound 2- 13 is then prepared by coupling to the benzoxazolyl boronate 2-12, for example in a Suzuki coupling.
58%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; N,N-dimethyl-formamide; for 2h;Reflux;	10556] The above reaction scheme illustrates the synthesis of a compound of the invention 2-13. Methylation of starting material 2-1 yields compound 2-2, which is subsequently reduced to the amine 2-3. In a separate reaction, compound 2-4 is converted to a salt, such as an HC1 salt, which is then reacted, for example, with 2-nitrovinyl-hydroxylamine to yield compound 2-6. Further cyclization yields compound 2-7. Halogenation with a reagent such as POd3 results in compound 2-8, which can be coupled with intermediate 2-3 to yield 2-9. The nitro moiety of 2-9 is subsequently reduced to an amine, and a further reaction with 4-nitrophenyl carbonochloridate results in the heterocycle 2-11. The desired compound 2-13 is then prepared by coupling to the benzoxazolyl boronate 2-12, for example in a Suzuki coupling.

Reference： [1]Patent: WO2012/116237,2012,A2 .Location in patent: Page/Page column 119-120
[2]Patent: US2015/320727,2015,A1 .Location in patent: Paragraph 0555; 0556
[3]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 75

6
[ 40925-68-6 ]
[ 1224844-66-9 ]

Reference： [1]Patent: WO2013/71272,2013,A1
[2]Patent: WO2013/23184,2013,A1
[3]Patent: WO2014/151147,2014,A1
[4]Patent: WO2014/151147,2014,A1
[5]Patent: US2014/357651,2014,A1
[6]Patent: US2014/357651,2014,A1
[7]Patent: US9174994,2015,B2
[8]Patent: US9174994,2015,B2
[9]Patent: CN105130973,2018,B

7
[ 1224844-66-9 ]
[ 1268454-23-4 ]

Reference： [1]Patent: WO2013/71272,2013,A1

8
[ 1224844-66-9 ]
(6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)(morpholino)methanone hydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/71272,2013,A1

9
[ 1224844-66-9 ]
C₁₉H₁₇N₅O₃*(x)H₂O₄S [ No CAS ]

Reference： [1]Patent: WO2013/71272,2013,A1

10
[ 1224844-66-9 ]
(x)C₇H₈O₃S*C₁₉H₁₇N₅O₃ [ No CAS ]

Reference： [1]Patent: WO2013/71272,2013,A1

11
[ 1224844-66-9 ]
(x)CH₄O₃S*C₁₉H₁₇N₅O₃ [ No CAS ]

Reference： [1]Patent: WO2013/71272,2013,A1

12
[ 1224844-66-9 ]
(x)C₂H₂O₄*C₁₉H₁₇N₅O₃ [ No CAS ]

Reference： [1]Patent: WO2013/71272,2013,A1

13
[ 1224844-66-9 ]
(x)C₂H₆O₄S*C₁₉H₁₇N₅O₃ [ No CAS ]

Reference： [1]Patent: WO2013/71272,2013,A1

14
[ 1224844-66-9 ]
(x)C₄H₇NO₄*C₁₉H₁₇N₅O₃ [ No CAS ]

Reference： [1]Patent: WO2013/71272,2013,A1

15
[ 1224844-66-9 ]
(x)C₄H₄O₄*C₁₉H₁₇N₅O₃ [ No CAS ]

Reference： [1]Patent: WO2013/71272,2013,A1

16
[ 1224844-66-9 ]
C₁₉H₁₇N₅O₃*(x)H₃O₄P [ No CAS ]

Reference： [1]Patent: WO2013/71272,2013,A1

17
[ 1224844-66-9 ]
(x)C₂H₆O₃S*C₁₉H₁₇N₅O₃ [ No CAS ]

Reference： [1]Patent: WO2013/71272,2013,A1

18
[ 1224844-66-9 ]
3-bromo-2-isopropyl-2H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]
[ 1422006-34-5 ]

Yield	Reaction Conditions	Operation in experiment
52%	With palladium diacetate; sodium carbonate; triphenylphosphine; In ethanol; water; N,N-dimethyl-formamide; at 80 - 90℃; for 1.5h;Inert atmosphere;	3-bromo-2-isopropyl-2H-pyrazolo[3,4-d]pyrimidin-4-amine 2a ( 500 mg, 1.95 mmol, 1.0 eq), <strong>[1224844-66-9]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine</strong> (1 g, 3.9 mmol, 2.0 eq), Pd(0Ac)2 (13110 mg, 0.59 mmol, 0.3 eq), PPh3 (308 mg, 1.17 mmol, 0.6 eq) and Na2C03 (1.03 g, 9. 75 mmol, 5.0 eq) weredissolved in DMF/EtOHIH20 (30 mL I lOmL I lOmL). The resulting mixture was degassed and back-filled withargon three times, and then stirred at 80 - 90 C under an argon atmosphere for 1.5 h. The reaction was completebased on TLC analysis. The mixture was concentrated in vacuo and the residue was purified by flash columnchromatography on silica gel (MeOH I DCM 1: 100 to 1:10) to afford the desired product 5-(4-amino-2-15 isopropyl-2H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine (Formula III) (300 mg, 52%) as a solid.

Reference： [1]Patent: WO2013/23184,2013,A1 .Location in patent: Paragraph 00241; 00242; 00243

19
[ 1224844-66-9 ]
C₁₃H₁₂BrN₃O₂ [ No CAS ]
C₂₀H₁₇N₅O₃ [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[2]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 74
[3]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 357; 358

20
[ 1224844-66-9 ]
[ 364793-54-4 ]
C₂₂H₁₃N₅O [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1

21
[ 1224844-66-9 ]
[ 364793-54-4 ]
C₁₇H₉ClN₄O [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[2]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 77
[3]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 365

22
4-bromo-3-amino-1H-indazole [ No CAS ]
[ 1224844-66-9 ]
C₁₄H₁₁N₅O [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[2]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 75
[3]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 361

23
[ 1224844-66-9 ]
[ 1692-15-5 ]
[ 602303-26-4 ]
C₁₉H₁₂N₄OS [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[2]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 361; 362

24
[ 1224844-66-9 ]
C₁₂H₁₂ClIN₂O₂ [ No CAS ]
C₁₉H₁₇ClN₄O₃ [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[2]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 76
[3]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 362; 363

25
[ 1224844-66-9 ]
C₁₂H₁₂ClIN₂O₂ [ No CAS ]
C₁₉H₁₃N₅O [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1

26
[ 1224844-66-9 ]
C₁₄H₁₃BrN₂O₂ [ No CAS ]
C₂₁H₁₈N₄O₃ [ No CAS ]

27
[ 474707-19-2 ]
[ 1224844-66-9 ]
C₂₁H₂₁N₅O [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[2]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 78
[3]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 367; 368

28
[ 106-41-2 ]
[ 1224844-66-9 ]

Reference： [1]Patent: WO2014/151147,2014,A1
[2]Patent: WO2014/151147,2014,A1
[3]Patent: US2014/357651,2014,A1
[4]Patent: US2014/357651,2014,A1
[5]Patent: US9174994,2015,B2
[6]Patent: US9174994,2015,B2
[7]Patent: CN105130973,2018,B

29
[ 7693-52-9 ]
[ 1224844-66-9 ]

30
[ 1404480-03-0 ]
[ 1224844-66-9 ]

Reference： [1]Patent: WO2014/151147,2014,A1
[2]Patent: US2014/357651,2014,A1
[3]Patent: US9174994,2015,B2

31
[ 1224844-66-9 ]
[ 64037-07-6 ]
C₁₄H₁₀N₄O₂ [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[2]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 76; 77
[3]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 363; 364

32
[ 1224844-66-9 ]
[ 1268453-31-1 ]

Reference： [1]Patent: WO2014/151147,2014,A1

33
[ 1224844-66-9 ]
C₁₈H₁₂N₆O [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1

34
[ 1224844-66-9 ]
C₁₈H₁₂N₆O [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1

35
[ 1224844-66-9 ]
C₁₈H₁₂N₆O [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1

36
[ 1224844-66-9 ]
[ 1268459-49-9 ]

Reference： [1]Patent: WO2014/151147,2014,A1

37
[ 1224844-66-9 ]
C₁₃H₈BrN₅O [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1

38
[ 1224844-66-9 ]
C₁₃H₈IN₅O [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1

39
[ 1224844-66-9 ]
C₁₃H₈BrN₅O [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1

40
[ 15864-32-1 ]
[ 1224844-66-9 ]
C₁₄H₁₀N₄OS [ No CAS ]

41
[ 1224844-66-9 ]
C₁₃H₁₅BrN₄O [ No CAS ]
C₂₀H₂₀N₆O₂ [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[2]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 68
[3]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 345; 346

42
[ 1224844-66-9 ]
[ 6775-78-6 ]
C₁₃H₉N₅O [ No CAS ]

43
[ 1224844-66-9 ]
C₁₂H₉ClN₄ [ No CAS ]
C₁₉H₁₄N₆O [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[2]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 69; 70
[3]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 349

44
[ 1224844-66-9 ]
C₁₀H₁₁ClN₄O [ No CAS ]
C₁₇H₁₆N₆O₂ [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[2]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 349; 350

45
[ 1224844-66-9 ]
[ 29274-24-6 ]
C₁₃H₉N₅O [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[2]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 71
[3]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 351

46
[ 96048-75-8 ]
[ 1224844-66-9 ]
C₂₀H₁₄N₄O [ No CAS ]

47
[ 1224844-66-9 ]
[ 1245649-58-4 ]
C₁₉H₁₈N₄O₂ [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[2]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 72
[3]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 353

48
[ 1224844-66-9 ]
C₁₄H₁₆BrN₃O [ No CAS ]
C₂₁H₂₁N₅O₂ [ No CAS ]

49
[ 1224844-66-9 ]
C₁₃H₁₃BrN₂O₂ [ No CAS ]
C₂₀H₁₈N₄O₃ [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[2]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 73
[3]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 355; 356

50
[ 916811-87-5 ]
[ 1224844-66-9 ]
C₁₉H₁₇N₅O₂ [ No CAS ]

51
[ 1224844-66-9 ]
C₁₄H₁₆BrN₃O [ No CAS ]
C₂₁H₂₁N₅O₂ [ No CAS ]

Reference： [1]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[2]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 73

52
[ 1224844-66-9 ]
C₁₄H₁₇BrN₄O [ No CAS ]
C₂₁H₂₂N₆O₂ [ No CAS ]

Reference： [1]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 72
[2]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 354

53
[ 1224844-66-9 ]
C₁₀H₅BrN₂ [ No CAS ]
C₁₇H₁₀N₄O [ No CAS ]

Reference： [1]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 74

54
[ 1224844-66-9 ]
[ 602303-26-4 ]
C₁₄H₈ClN₃OS [ No CAS ]

Reference： [1]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 76

55
[ 1224844-66-9 ]
C₁₁H₁₂ClN₃O [ No CAS ]
C₁₈H₁₇N₅O₂ [ No CAS ]

Reference： [1]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 70

56
[ 7647-01-0 ]
[ 1224844-66-9 ]
[ 1404480-15-4 ]

Reference： [1]Patent: US9174994,2015,B2 .Location in patent: Page/Page column 120

57
[ 1224844-66-9 ]
C₁₄H₁₈BrN₃O [ No CAS ]
C₂₁H₂₃N₅O₂ [ No CAS ]

Reference： [1]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 357; 358

58
[ 1224844-66-9 ]
1-(4-chlorobutyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]
5-(4-amino-1-(4-chlorobutyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 110℃; for 3h;Inert atmosphere;	Preparation of 5-(4-amino-l-(4-chlorobutyl)-lH-pyrazolo[3,4-< ]pyrimidin-3- yl)benzo[d]oxazol-2-amine 9a. To a bi-phasic suspension of l-(4-chlorobutyl)-3-iodo-lH- pyrazolo[3,4-i/]pyrimidin-4-amine (8a) (703 mg, 2.00 mmol), 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzo[d]oxazol-2-amine (780 mg, 3.00 mmol) (prepared by a similar method to that described in WO2010/051042A1), and saturated aqueous a2C03 solution (10 mL) in DME (30 mL) and water (10 mL) was added tetrakis(triphenylphosphine)palladium (0) (232 mg, 200 muiotaetaomicron) at room temperature under argon atmosphere. The mixture was stirred at 1 10 C for 3 h. It was then cooled and partitioned between EtOAc (200 mL) and water (100 mL). The aqueous layer was separated and extracted with EtOAc (100 mL). The organic layers were combined, washed with brine (50 mL) and dried over anhydrous MgS04. The insoluble was filtered off and the filtrate was concentrated in vacuo. The crude material was purified by silica gel column chromatography (basic silica gel: 25 g, solvent: 20% MeOH in EtOAc (100 mL)). The desired fractions were combined and the obtained solid was triturated with EtOAc (50 mL) for 30 min. The precipitate was collected by filtration. Drying the solid gave the titled compound (445 mg, 62%) as a pale beige solid. [0322] LH NMR (400 MHz, DMSO-i/6) delta 8.25 (1H, s), 7.53 (2H, s), 7.47 (1H, d, J= 8.0 Hz), 7.41 (1H, br s), 7.25 (1H, dd, J= 8.4, 1.2 Hz), 4.37 (2H, t, J= 6.8 Hz), 3.67 (2H, t, J= 6.8 Hz), 1.93-2.02 (2H, m), 1.67-1.76 (2H, m), NH2 protons were not identified. [0323] LC-MS (ESI) m/z = 358.20 (M+H)+.

Reference： [1]Patent: WO2016/40806,2016,A1 .Location in patent: Paragraph 0321-0323

59
[ 1224844-66-9 ]
tert-butyl (4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)carbamate [ No CAS ]
tert-butyl (4-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 110℃; for 3h;Inert atmosphere;	Preparation of tert-butyl (4-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-lH- pyrazolo[3,4-< \|pyrimidin-l-yl)butyl)carbamate 9b. To a bi-phasic suspension of tert-butyl (4-(4-amino-3-iodo-lH-pyrazolo[3,4-i/]pyrimidin-l-yl)butyl)carbamate (8b) (435 mg, 1.00 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (390 mg, 1.50 mmol), and a2C03 (530 mg, 5.00 mmol) in DME (10 mL) and water (5 mL) was added tetrakis(triphenylphosphine)palladium (0) (116 mg, 100 muiotaetaomicron) at room temperature under argon atmosphere. The mixture was stirred at 1 10 C for 3 h. It was then cooled and partitioned between EtOAc (90 mL) and water (30 mL). The aqueous layer was separated and extracted with EtOAc (2x30 mL). The organic layers were combined, washed with brine (2x30 mL) and dried over anhydrous MgS04. The insoluble was filtered off and the filtrate was concentrated in vacuo. The crude material was purified by silica gel column chromatography (silica gel: 75 g, solvent: 50% EtOAc in hexanes (400 mL) followed by 20% MeOH in EtOAc (800 mL)). The desired fractions were combined and evaporated in vacuo. The obtained solid was recrystallized from MeOH/water to give the titled compound (332 mg, 76%) as a colorless solid. [0336] 'H NMR (400 MHz, DMSO-i) delta 8.23 (1H, s), 7.52 (2H, s), 7.46 (1H, d, J= 8.0 Hz), 7.41 (1H, s), 7.23 (1H, dd, J= 8.0, 1.2 Hz), 6.79 (1H, t, J= 5.6 Hz), 4.32 (2H, t, J= 5.6 Hz), 3.26-3.33 (2H, m), 2.88-2.96 (2H, m), 1.77-1.87 (2H, m), 1.35 (9H, s), NH2 protons were not identified. [0337] LC-MS (ESI) m/z = 439.28 (M+H)+.

Reference： [1]Patent: WO2016/40806,2016,A1 .Location in patent: Paragraph 0335-0337

60
[ 1224844-66-9 ]
C₁₁H₁₄IN₅O₂ [ No CAS ]
C₁₈H₁₉N₇O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 110℃; for 3h;Inert atmosphere;	Preparation of 5-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-lH-pyrazolo[3,4- < [pyrimidin-l-yl)pentanoic acid 9c. To a bi-phasic suspension of 5-(4-amino-3-iodo-lH- pyrazolo[3,4-i/]pyrimidin-l-yl)pentanoic acid (8c) (375 mg, 1.00 mmol), 5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (390 mg, 1.50 mmol), and saturated aqueous a2C( solution (2.5 mL) in DME (10 mL) and water (2.5 mL) was added tetrakis(triphenylphosphine)palladium (0) (116 mg, 100 mu mol) at room temperature under argon atmosphere. The mixture was stirred at 1 10 C for 3 h. The reaction mixture was cooled to 60 C and diluted with MeOH (10 mL) and THF (10 mL). To the reaction mixture was added 4 M aqueous LiOH solution (5 mL). The mixture was stirred at 60 C for additional 2 h. It was then cooled and acidified using AcOH to adjust pH to be 3-4. The mixture was partitioned between EtOAc (200 mL) and water (10 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous MgS04. The insoluble was filtered off and the filtrate was concentrated in vacuo. The crude material was purified by silica gel column chromatography (silica gel: 25 g, solvent: 2-30% MeOH in ((). The desired fractions were combined and evaporated in vacuo. The obtained solid was triturated with 20% EtOAc in hexanes. The resulting precipitate was collected by filtration. Drying the solid gave the titled compound (207 mg, 56%) as a pale pink powder. [0350] lH NMR (400 MHz, DMSO-i) delta 12.00 (1H, s), 8.24 (1H, s), 7.52 (2H, s), 7.46 (1H, d, J= 8.0Hz), 7.41 (1H, d, J= 1.6 Hz), 7.24 (1H, dd, J= 8.0, 1.6 Hz), 4.33 (2H, t, J= 6.8 Hz), 2.25 (2H, t, J= 7.2 Hz), 1.82-1.91 (2H, m), 1.44-1.53 (2H, m), 2H protons were not identified. [0351] LC-MS (ESI) m/z = 368.22 (M+H)+.

Reference： [1]Patent: WO2016/40806,2016,A1 .Location in patent: Paragraph 0349-0351

61
[ 1224844-66-9 ]
5-bromo-N,N-bis(4-methoxybenzyl)benzo[d]oxazol-2-amine [ No CAS ]
N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%		Step 2: N,N-Bis(4-methoxybenzyl)-<strong>[1224844-66-9]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine</strong> The title compound (1.06 g, 94% yield) was generated from 5-bromo-N,N-bis(4-methoxybenzyl)benzo[d]oxazol-2-amine (1.02 g, 2.25 mmol) following a procedure analogous to Example 204, step 7. LCMS (ESI): [M+H]+=501.